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An Application to Recommend That Fixed Dose Combination Therapy AN APPLICATION TO RECOMMEND THAT FIXED DOSE COMBINATION THERAPY BE ADDED TO THE WHO MODEL LIST OF ESSENTIAL MEDICINES FOR SECONDARY PREVENTION OF CARDIOVASCULAR DISEASE (ISCHEMIC HEART DISEASE AND THROMBOTIC STROKE) (12) Mark D. Huffman, MD, MPH, Northwestern University Feinberg School of Medicine, Chicago, USA Shanthi Mendis, MBBS, MD, FRCP, World Health Organization, Geneva, Switzerland Valentin Fuster, MD, PhD, Mount Sinai School of Medicine, New York, USA Anthony Rodgers, MD, The George Institute, Sydney, Australia Sidney C. Smith, Jr MD, University of North Carolina, Chapel Hill, NC, USA Salim Yusuf, MD, DPhil, MRCP, Population Health Research Institute, McMaster University, Hamilton, Canada 1 1. Executive Summary The World Health Organization (WHO) has recently announced its “25 by 25” target of reducing the burden of premature (<70 years) mortality from non-communicable, chronic diseases (NCDs) by 25% by the year 2025. Cardiovascular diseases (CVD), including ischemic heart disease and stroke, are the leading causes of death worldwide, yet less than half of all patients with prior disease take any medication for CVD secondary prevention and control. Fixed dose combination therapy including aspirin, beta-blockers, ACE-inhibitors, and statins have been advocated by the WHO for CVD secondary prevention since 2001 given the benefits in terms of efficacy, adherence, scalability, and cost-effectiveness. Several versions of fixed dose combination therapy for CVD secondary prevention have been developed and studied within the past few years. Recent clinical trials have demonstrated similar bioequivalence with similar (or greater) reductions in risk factors as well as a 33% increase in adherence compared with usual care in CVD secondary prevention. Given the urgent need for improved CVD prevention and control, we propose the inclusion of fixed dose combination therapies outlined below for CVD secondary prevention in the WHO Model List of Essential Medicines. 2. Name of the focal point in WHO submitting or supporting the application Dr. Shanthi Mendis, Coordinator, Chronic Disease Prevention and Management. 3. Name of the organizations consulted and/or supporting the application Individuals on behalf of organizations supporting the application are listed below (in alphabetical order): Name Institute Country Attaran, Amir University of Ottawa Canada Avezum, Alvaro Dante Pazzanese Institute of Cardiology Brazil Baigent, Colin Clinical Trials Service Unit United Kingdom Beaglehole, Robert University of Auckland New Zealand Bots, Michiel University Medical Center Utrecht Netherlands Bovet, Pascal Institut Universitaire de Médecine Sociale et Preventive Switzerland Bullen, Chris University of Auckland New Zealand Chow, Clara The George Institute for Global Health Australia Dans, Antonio University of the Philippines Philippines Diaz, Rafael Estudios Cardiologicos Latino America Argentina 2 Elley, Raina University of Auckland New Zealand Enas, Enas CADI Research Foundation United States Gaziano, Tom Harvard School of Public Health United States Gerstein, Hertzel McMaster University Canada Grassi, Guido Università degli Studi Milano-Bicocca Italy Grobbee, Diederick University Medical Center Utrecht Netherlands Hart, Robert McMaster University Canada Keltai, Matyas Hungarian Institute of Cardiology Hungary Kengne, Andre South African Medical Research Council South Africa Lafeber, Melvin University Medical Center Utrecht Netherlands Liu, Lisheng National Center of Cardiovascular Diseases China Lonn, Eva McMaster University Canada Lopez-Jaramillo, Patricio Fundacion Oftalmológica de Santander Colombia Mayosi, Bongani Pan African Society of Cardiology South Africa McKee, Martin London School of Hygiene and Tropical Medicine United Kingdom Mills, Ed University of Ottawa Canada Narayan, Venkat Emory University United States Neaton, Jim University of Minnesota United States Niessen, Louis Johns Hopkins University United States Paccaud, Fred Institut Universitaire de Médecine Sociale et Preventive Switzerland Pais, Prem St John’s National Academy of Health Sciences India Prabhakaran, D Centre for Chronic Disease Control India Reddy, K. Srinath Public Health Foundation of India India Sadanandan, Rajeev Government of Kerala India Sanz, Gines Centro Nacional de Investigaciones Cardiovasculares Spain Schwalm, JD McMaster University Canada Selak, Vanessa University of Auckland New Zealand Smith, Richard UnitedHealth Chronic Disease Initiative United Kingdom 3 Smith, Sidney World Heart Federation Switzerland Szuba, Andrzej Wroclaw Medical University Poland Teo, Koon McMaster University Canada Varigos, John Monash University Australia Vijay, Kris Cardio Renal Society of America United States Webster, Ruth The George Institute for Global Health Australia Weissberg, Jed Kaiser Permanente United States Wood, Bobbe Heart & Stroke Foundation of Canada Canada Xavier, Denis St John’s National Academy of Health Sciences India Yeates, Karen Queen’s University Canada Yusoff, Khalid Universiti Teknologi MARA Malaysia Maria Skłodowska-Curie Memorial Cancer Center and Zatonski, Witold Poland Institute of Oncology Zhu, Jun Chinese Academy of Medical Sciences China 4. International Proprietary Name (INN) a) Indian Polycap (aspirin, simvastatin, ramipril, atenolol, hydrochlorothiazide) b) Sincronium (México)/Trinomia (rest of the world) (aspirin, simvastatin, ramipril) c) Red Heart Pill 1 (aspirin, simvastatin, lisinopril, atenolol) and Red Heart Pill 2 (aspirin, simvastatin, lisinopril, hydrochlorothiazide) 5. Formulation proposed for inclusion a) Indian Polycap (low dose: aspirin 100 mg, simvastatin 20 mg, ramipril 5 mg, atenolol 50 mg, hydrochlorothiazide 12.5 mg; high-dose: aspirin 200 mg, simvastatin 40 mg, ramipril 10 mg, atenolol 100 mg, and hydrochlorothiazide 25 mg) b) Trinomia/Sincronium (aspirin 100 mg, simvastatin 40 mg, and ramipril (2.5 mg, 5 mg, or 10 mg)) c) Red Heart Pill 1 (aspirin 75mg, simvastatin (20 or 40mg), lisinopril 10mg, atenolol 50mg) and Red Heart Pill 2 (aspirin 75mg, simvastatin (20 or 40mg), lisinopril 10 mg, hydrochlorothiazide 12.5 mg) 6. International availability The Indian Polycap (Cadila) is currently available in India. 4 Trinomia/Sincronium (Ferrer) is available in Guatemala and México and will soon be available in Argentina and Nicaragua. Regulatory submissions for the Red Heart Pills 1 and 2 (Dr. Reddy’s Laboratories, Ltd.) have been developed and are planned for submission by early 2013. As of November 2012, the Indian Polycap and Trinomia/Sincronium pill are manufactured by companies in two countries (Table 1). The George Institute for Global Health is now negotiating a global license for the Red Heart Pill products following a recent decision by the current manufacturer (Dr. Reddy’s Laboratories, Ltd.) not to proceed with taking the products to market because of existing regulatory requirements. The George Institute has nearly completed its licensing agreement with Dr. Reddy’s Laboratories, Ltd. for production through an alternate manufacturer. Table 1. List of countries in which indicated drugs are manufactured and/or formulated. Company Manufacturing Company Manufacturing Country Indian Polycap Trinomia/Sincronium India Cadila Pharmaceuticals, Ltd. Spain Ferrer International 7. Listing as individual medicine or representative of therapeutic group Fixed dose combinations as listed above with the goal of future fixed dose combinations to be added to the Model List of Essential Medicines to update the Model List. Alternatively, fixed dose combination therapy could be considered under the “square box” category to indicate similar clinical efficacy. 8. Information Supporting the Public Health Relevance The World Health Organization (WHO) has recently announced targets for reducing the number of premature deaths (<70 years) due to non-communicable, chronic diseases (NCDs) by 25% by the year 2025.(1) These targets have been preceded by other WHO goals of reducing the burden of not only premature death but also disability from NCDs,(2) which were formalized as a result of the resulting Political Declaration from the 2011 United Nations High Level Meeting on NCDs.(3) Since cardiovascular diseases (CVD) are the leading causes of mortality in the world and since more than 80% of CVD deaths occur in low- and middle-income countries (LMICs),(4) CVD treatment and control are crucial to reaching these WHO targets. If current trends continue, CVD morbidity and mortality are projected to increase substantially in the coming decades.(5) However, CVD secondary prevention with fixed dose combination therapy has been deemed a “best buy” by the WHO(6) and organizations such as the NCD Alliance(7) given its efficacy, adherence, scalability and cost-effectiveness.(8) More than half of patients with prior ischemic heart disease or stroke receive no secondary medications,(9) yet the WHO’s recent indicators to reach its “25 by 25” target include provision that 50% of eligible people receive drugs to prevent heart attacks and strokes. 5 A large amount of evidence supports the use of pharmacological treatment for the secondary prevention of cardiovascular death in patients with prior CVD events. Drugs including antiplatelet agents,(10) beta-blockers,(11) lipid-lowering agents,(12) and angiotensin-converting-enzyme inhibitors(13) have all demonstrated improvements in mortality and morbidity individually and are recommended for secondary prevention of CVD by a diverse group of professional organizations.(14) However, substantial gaps in coverage
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